Rationale, design and conduct of a randomised controlled trial evaluating a primary care-based complex intervention to improve the quality of life of heart failure patients: HICMan (Heidelberg Integrated Case Management) : study protocol

Background: Chronic congestive heart failure (CHF) is a complex disease with rising prevalence, compromised quality of life (QoL), unplanned hospital admissions, high mortality and therefore high burden of illness. The delivery of care for these patients has been criticized and new strategies addressing crucial domains of care have been shown to be effective on patients' health outcomes, although these trials were conducted in secondary care or in highly organised Health Maintenance Organisations. It remains unclear whether a comprehensive primary care-based case management for the treating general practitioner (GP) can improve patients' QoL. Methods/Design: HICMan is a randomised controlled trial with patients as the unit of randomisation. Aim is to evaluate a structured, standardized and comprehensive complex intervention for patients with CHF in a 12-months follow-up trial. Patients from intervention group receive specific patient leaflets and documentation booklets as well as regular monitoring and screening by a prior trained practice nurse, who gives feedback to the GP upon urgency. Monitoring and screening address aspects of disease-specific selfmanagement, (non)pharmacological adherence and psychosomatic and geriatric comorbidity. GPs are invited to provide a tailored structured counselling 4 times during the trial and receive an additional feedback on pharmacotherapy relevant to prognosis (data of baseline documentation). Patients from control group receive usual care by their GPs, who were introduced to guidelineoriented management and a tailored health counselling concept. Main outcome measurement for patients' QoL is the scale physical functioning of the SF-36 health questionnaire in a 12-month follow-up. Secondary outcomes are the disease specific QoL measured by the Kansas City Cardiomyopathy questionnaire (KCCQ), depression and anxiety disorders (PHQ-9, GAD-7), adherence (EHFScBS and SANA), quality of care measured by an adapted version of the Patient Chronic Illness Assessment of Care questionnaire (PACIC) and NTproBNP. In addition, comprehensive clinical data are collected about health status, comorbidity, medication and health care utilisation. Discussion: As the targeted patient group is mostly cared for and treated by GPs, a comprehensive primary care-based guideline implementation including somatic, psychosomatic and organisational aspects of the delivery of care (HICMAn) is a promising intervention applying proven strategies for optimal care. Trial registration: Current Controlled Trials ISRCTN30822978

Isolation and fine mapping of Rps6: An intermediate host resistance gene in barley to wheat stripe rust

A plant may be considered a nonhost of a pathogen if all known genotypes of a plant species are resistant to all known isolates of a pathogen species. However, if a small number of genotypes are susceptible to some known isolates of a pathogen species this plant maybe considered an intermediate host. Barley (Hordeum vulgare) is an intermediate host for Puccinia striiformis f. sp. tritici (Pst), the causal agent of wheat stripe rust. We wanted to understand the genetic architecture underlying resistance to Pst and to determine whether any overlap exists with resistance to the host pathogen, Puccinia striiformis f. sp. hordei (Psh). We mapped Pst resistance to chromosome 7H and show that host and intermediate host resistance is genetically uncoupled. Therefore, we designate this resistance locus Rps6. We used phenotypic and genotypic selection on F2:3 families to isolate Rps6 and fine mapped the locus to a 0.1 cM region. Anchoring of the Rps6 locus to the barley physical map placed the region on two adjacent fingerprinted contigs. Efforts are now underway to sequence the minimal tiling path and to delimit the physical region harbouring Rps6. This will facilitate additional marker development and permit identification of candidate genes in the region

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Phenotypic Variation and Bistable Switching in Bacteria

Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.

Estimating Individual Exposure to Malaria Using Local Prevalence of Malaria Infection in the Field

BACKGROUND: Heterogeneity in malaria exposure complicates survival analyses of vaccine efficacy trials and confounds the association between immune correlates of protection and malaria infection in longitudinal studies. Analysis may be facilitated by taking into account the variability in individual exposure levels, but it is unclear how exposure can be estimated at an individual level. METHOD AND FINDINGS: We studied three cohorts (Chonyi, Junju and Ngerenya) in Kilifi District, Kenya to assess measures of malaria exposure. Prospective data were available on malaria episodes, geospatial coordinates, proximity to infected and uninfected individuals and residence in predefined malaria hotspots for 2,425 individuals. Antibody levels to the malaria antigens AMA1 and MSP1(142) were available for 291 children from Junju. We calculated distance-weighted local prevalence of malaria infection within 1 km radius as a marker of individual's malaria exposure. We used multivariable modified Poisson regression model to assess the discriminatory power of these markers for malaria infection (i.e. asymptomatic parasitaemia or clinical malaria). The area under the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of the models. Local malaria prevalence within 1 km radius and AMA1 and MSP1(142) antibodies levels were independently associated with malaria infection. Weighted local malaria prevalence had an area under ROC curve of 0.72 (95%CI: 0.66-0.73), 0.71 (95%CI: 0.69-0.73) and 0.82 (95%CI: 0.80-0.83) among cohorts in Chonyi, Junju and Ngerenya respectively. In a small subset of children from Junju, a model incorporating weighted local malaria prevalence with AMA1 and MSP1(142) antibody levels provided an AUC of 0.83 (95%CI: 0.79-0.88). CONCLUSION: We have proposed an approach to estimating the intensity of an individual's malaria exposure in the field. The weighted local malaria prevalence can be used as individual marker of malaria exposure in malaria vaccine trials and longitudinal studies of natural immunity to malaria

A four-kallikrein panel for the prediction of repeat prostate biopsy: data from the European Randomized Study of Prostate Cancer Screening in Rotterdam, Netherlands

Background: Most men with elevated levels of prostate-specific antigen (PSA) do not have prostate cancer, leading to a large number of unnecessary biopsies. A statistical model based on a panel of four kallikreins has been shown to predict the outcome of a first prostate biopsy. In this study, we apply the model to an independent data set of men with previous negative biopsy but persistently elevated PSA. Methods: The study cohort consisted of 925 men with a previous negative prostate biopsy and elevated PSA (≥3 ng ml-1), with 110 prostate cancers detected (12%). A previously published statistical model was applied, with recalibration to reflect the lower positive biopsy rates on rebiopsy. Results: The full-kallikrein panel had higher discriminative accuracy than PSA and DRE alone, with area under the curve (AUC) improving from 0.58 (95% confidence interval (CI): 0.52, 0.64) to 0.68 (95% CI: 0.62, 0.74), P<0.001, and high-grade cancer (Gleason 7) at biopsy with AUC improving from 0.76 (95% CI: 0.64, 0.89) to 0.87 (95% CI: 0.81, 0.94), P<0.003). Application of the panel to 1000 men with persistently elevated PSA after initial negative biopsy, at a 15% risk threshold would reduce the number of biopsies by 712; would miss (or delay) the diagnosis of 53 cancers, of which only 3 would be Gleason 7 and the rest Gleason 6 or less. Conclusions: Our data constitute an external validation of a previously published model. The four-kallikrein panel predicts the result of repeat prostate biopsy in men with elevated PSA while dramatically decreasing unnecessary biopsies

Dynamical Boson Stars

The idea of stable, localized bundles of energy has strong appeal as a model for particles. In the 1950s John Wheeler envisioned such bundles as smooth configurations of electromagnetic energy that he called {\em geons}, but none were found. Instead, particle-like solutions were found in the late 1960s with the addition of a scalar field, and these were given the name {\em boson stars}. Since then, boson stars find use in a wide variety of models as sources of dark matter, as black hole mimickers, in simple models of binary systems, and as a tool in finding black holes in higher dimensions with only a single killing vector. We discuss important varieties of boson stars, their dynamic properties, and some of their uses, concentrating on recent efforts.Comment: 79 pages, 25 figures, invited review for Living Reviews in Relativity; major revision in 201

Effects of an interactive CD-program on 6 months readmission rate in patients with heart failure – a randomised, controlled trial [NCT00311194]

BACKGROUND: Disease-management programmes including patient education have promoted improvement in outcome for patients with heart failure. However, there is sparse evidence concerning which component is essential for success, and very little is known regarding the validity of methods or material used for the education. METHODS: Effects of standard information to heart failure patients given prior to discharge from hospital were compared with additional education by an interactive program on all-cause readmission or death within 6 months. As a secondary endpoint, patients' general knowledge of heart failure and its treatment was tested after 2 months. RESULTS: Two hundred and thirty patients were randomised to standard information (S) or additional CD-ROM education (E). In (S) 52 % reached the endpoint vs. 49 % in (E). This difference was not significant. Of those who completed the questionnaire (37 %), patients in (E) achieved better knowledge and a marginally better outcome. CONCLUSION: The lack of effect on the readmission rate could be due to an insufficient sample size but might also indicate that in pharmacologically well-treated patients there is little room for altering the course of the condition. As there was some indication that patients who knew more about their condition might fare better, the place for intensive education and support of heart failure patients has yet to be determined

Exclusive Leptoproduction of rho^0 Mesons from Hydrogen at Intermediate Virtual Photon Energies

Measurements of the cross section for exclusive virtual-photoproduction of rho^0 mesons from hydrogen are reported. The data were collected by the HERMES experiment using 27.5 GeV positrons incident on a hydrogen gas target in the HERA storage ring. The invariant mass W of the photon-nucleon system ranges from 4.0 to 6.0 GeV, while the negative squared four-momentum Q^2 of the virtual photon varies from 0.7 to 5.0 GeV^2. The present data together with most of the previous data at W > 4 GeV are well described by a model that infers the W-dependence of the cross section from the dependence on the Bjorken scaling variable x of the unpolarized structure function for deep-inelastic scattering. In addition, a model calculation based on Off-Forward Parton Distributions gives a fairly good account of the longitudinal component of the rho^0 production cross section for Q^2 > 2 GeV^2.Comment: 10 pages, 6 embedded figures, LaTeX for SVJour(epj) document class. Revisions: curves added to Fig. 1, several clarifications added to tex